Born Again

What's the fastest, cheapest way to develop a wonder drug? Recycle an old one.

So much depends upon a lone water molecule. Take the alkaloid C17H19NO3, better known as morphine, a painkiller no hospital can do without. Lop off two atoms of hydrogen and one of oxygen, as German chemist Augustus Matthiessen first did in 1869, and you're left with apomorphine, which is less effective at dulling pain than a shot of Southern Comfort. Instead, its most obvious effect is to cause rapid and severe vomiting – useful when a toddler drinks Liquid-Plumr, perhaps, but hardly the stuff of pharmaceutical legend.

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Like so many compounds concocted during that first golden age of drug research, when chemists mixed and matched molecules with the joyful abandon of Julia Child whipping up figgy pudding, apomorphine was a triumph of chemistry but a failure of product development. Matthiessen's employer, Friedrich Bayer & Co., was primarily a manufacturer of textile dyes and a good three decades away from its landmark discoveries of aspirin and heroin. Unsure how to market the opiate derivative, Bayer peddled apomorphine as a purgative, alongside such fashionable Victorian preparations as castor oil. The drug was later tried as a treatment for brain disorders, schizophrenia, even homosexuality. Alas, a miracle cure it was not.

Now, after 134 years of trial and error, apomorphine may finally have found its niche – as bioengineered Spanish fly, and financial savior of Nastech, a small biotech company in Bothell, Washington. Seven years ago, as he thumbed through notes from an obscure schizophrenia study, Nastech's former CEO, the now-deceased Vincent Romeo, noted an odd side effect of apomorphine: When they weren't hugging the john, users experienced heightened sexual arousal. If he could eliminate that unromantic barfing, Romeo surmised, he'd have the chemical equivalent of a Barry White record. Considering that wannabe Don and Donna Juans spend billions on products ranging from Viagra to pulverized tiger penis, this kind of blockbuster could turn Nastech from a perennial money pit into a market star.

For biotech companies, reviving remedies that have fallen out of patent may be just what the doctor ordered. Collapsing stock values have made capital scarce. Big Pharma is increasingly reluctant to pitch in, and investors are no longer content to gamble on drugs with a dark horse's chance of hitting the market in 2012. The price of developing a new, proprietary drug starts at $150 million, a sum beyond the reach of all but a few biotech firms. Fine-tuning public-domain compounds that have been studied for decades is cheaper, faster, and lower-risk. Nastech expects its apomorphine program to cost one-twentieth the tab for bringing a new drug to market.

Glamour be damned, then, as researchers abandon their labs for the library, hunting for discards to be poked, prodded, and kneaded into new products. If a Victorian vagrant like apomorphine can be reborn as Viagra Plus, perhaps those dusty tomes contain other profitable secrets – secrets that might prove to be the teetering biotech industry's short-term salvation.

Apomorphine's first go-around as a wonder drug dates to the days of the Spanish-American War, when doctors discovered its ability to alleviate symptoms of advanced Parkinson's disease. In the brain, apomorphine mimics the action of dopamine, a neurotransmitter lacking in Parkinson's sufferers. But the drug's short half-life means that injections must be administered every two hours or so, and apomorphine becomes less effective as the malady progresses. Other dopamine surrogates, such as L-dopa, though imperfect, eventually pushed apomorphine to the margin of the anti-Parkinson's arsenal.

The libido-stirring powers of such substances were an open secret among Parkinson's researchers, but decorum prevented them from formally recording the effect. Meanwhile, psychiatrists during the '60s used apomorphine as a "cure" for homosexuality, then classified as a mental disorder. In a bit of aversion therapy straight out of A Clockwork Orange, a patient was given a shot of apomorphine, then forced to view homoerotic photos until nausea kicked in. It's unclear whether the orchestrators of these futile sessions considered the attendant erections a vital part of the therapy or were oblivious to their occurrence.

Vincent Romeo's eureka moment came while perusing a study of apomorphine that mentioned erections in passing. But unlike Viagra, which merely inflates the vessels around the penis, apomorphine works its magic directly on the brain. It targets receptors in the hypothalamus, the neural region responsible for primitive impulses including hunger and sexual longing. Users report heightened awareness of sensory stimuli; deep green eyes or pouty lips suddenly cause sparks.

Nastech claims the effect isn't limited to males. "Drugs that work on the hypothalamus ought to be very good with female sexual dysfunction, too," says Steven Quay, who succeeded Romeo as CEO in 2000. A 1999 Journal of the American Medical Association study asserted that 43 percent of American women experience sexual dysfunction at least once a year. If apomorphine can help both genders, imagine the marketing edge it will have over Viagra.

But what about the drug's nasty side effect? Quay intends to dodge stomach upset by sending apomorphine directly to the brain. Nastech's mainstay is tweaking medications so they can be administered via nasal sprays instead of pills – a more felicitous delivery method for pharmaceuticals that are metabolized by the liver or upset the gut, as apomorphine does. The company's biodelivery system was designed to coax the body into accepting large-molecule therapeutic proteins and peptides. These substances have a tough time passing through gastrointestinal membranes and tend to get gobbled up by digestive enzymes. They can be injected, but the nose is a simpler, safer point of entry.

Nonetheless, the path from nostril to gray matter isn't a cakewalk. The cellular barriers that protect the brain are held together by a network of proteins called tight junctions. "It's like a cobblestone street, and the mortar between the stones is the tight junction," explains Quay, a former faculty member at Stanford Medical School with 41 drug patents to his name. Until recently, the only way to traverse these gaps was to push past them, risking tissue damage in the process. (Thus, the bloody noses often seen in cocaine abusers.) Nastech has developed a more artful method, which involves mixing the main payload with extra molecules – modulators, in biospeak – that open the tight junctions temporarily. This gives large molecules a clear path to the central nervous system.

Nastech's big idea is to adapt this system to apomorphine. The hope, borne out so far in clinical trials, is that shooting apomorphine through the tight junctions will prevent stomach upset. If the medicine can be delivered directly to the hypothalamus without having to ramble through the digestive tract, heavy petting can begin sans nausea.

The biotech business desperately needs a different approach, one capable of producing compounds that measure up to the industry's promise – and if rehabilitating old drugs does the trick, so be it. For all the hoopla, genomics has done nothing to accelerate drug development. It'll be a decade, at least, before gene-specific medicines enter the late-stage pipeline, and getting them there will take huge investments of time and money, two increasingly elusive resources.

The 1990s heyday, when the likes of Bristol-Myers Squibb blew billions on untested biotech elixirs, seems like eons ago. The Nasdaq Biotech Index lost more than half its value in 2002 alone. Venture capitalists have fled, causing funding to plummet by nearly 40 percent between the second and third quarters of last year. And Big Pharma, stuck with its own headaches over expiring patents and FDA red tape, is no longer so eager to rain cash upon every Johnny-come-lately with a fresh idea.

So fresh ideas are out, and crusty retreads are in. Consider thalidomide, a popular remedy for morning sickness until the early 1960s, when it was found to cause severe birth defects. Now the drug – in its original form – is being tested on multiple myeloma, a lethal blood cancer. It has already been approved for leprosy.

Bringing such medicines to market can be remarkably economical. Ownership has long since lapsed into the public domain, so there's no need for royalty payments or other accommodations for intellectual property rights. Plus, they've been studied, formulated, and tested before, giving developers a tremendous head start.

"If a drug has a long history, you're going to have a huge safety database," says Janice Reichert, a researcher at the Tufts Center for the Study of Drug Development. "The more advanced knowledge you have going into the clinical trials process, the more likely you are to get it done quickly and efficiently."

Among the more intriguing castoffs back in vogue is gamma-hydroxybutyrate, aka GHB, a once-promising anesthetic that was booted from the pharmacopoeia for causing respiratory distress. Inspired by research into precisely how the body metabolizes GHB, Minneapolis-based Orphan Medical found that, when combined with water and malic acid, the potentially lethal salt works wonders as a treatment for cataplexy, a muscle-depleting condition associated with narcolepsy. The FDA approved Orphan's concoction last July.

Paratek, a Boston-based biopharmaceutical outfit, is adapting tetracyclines, a 50-year-old class of antibiotics largely abandoned in the '80s, when bacteria began developing resistance to them. The company is amping up potency by adding molecules that are lethal to the bacterial variants. The modified tetracyclines are thus classified as bactericidal, as opposed to their bacteriostatic forebears, which merely arrested growth. Even more promising is research into genetic master switches that control the resistance of bugs like salmonella and E. coli. Paratek VP Dennis Tanaka believes tetracyclines can be tuned to flip these switches, making superbugs easy targets.

Then there's Bacillus Calmette-Gu�rin, a tuberculosis vaccine first culled from potatoes in the 1920s. Its effectiveness can be charitably described as mediocre; though still used in developing nations, BCG is largely disdained in the West. That may soon change, however, thanks to Marcus Horwitz, a UCLA researcher who has enhanced the vaccine with a protein-secreting gene that instructs the immune system to overproduce TB-fighting cells. Early clinical trials on the recombinant vaccine, owned by the university, are slated to begin shortly.

Regulatory approval is always a crapshoot, but pharmaceutical reruns have better odds than new compounds. Only 20 percent of drugs tested on animals – the first step in clinical trials – eventually earn FDA approval. Quay claims the figure is "arguably 100 percent" for drugs that have been on the market before in other forms, and although this may be an exaggeration, FDA observers agree that known quantities have a much easier time passing muster.

If nothing else, the buzz on apomorphine has allowed Nastech to survive the biotech crunch in high style. In February 2002, Quay struck a licensing agreement with Pharmacia, giving the Xanax maker the exclusive right to market intranasal apomorphine in exchange for royalties. In return, Pharmacia agreed to purchase 250,000 shares of Nastech stock at $20 each, well above last year's average of about $13. The Federal Trade Commission forced Pharmacia to divest its interest in apomorphine to clear the way for its proposed merger with Pfizer, maker of Viagra. But Pharmacia kept the stock, and now Nastech is free to cut a more lucrative deal with a different Big Pharma sugar daddy, thanks to apomorphine's strong performance in recent clinical trials. If all goes according to plan, would-be swains will have squeeze bottles in hand by 2006.

Biotech is usually viewed as medicine's avant-garde. And, to be sure, many valiant companies are on the front line, leading the way to cures for cancer and inherited diseases like cystic fibrosis and muscular dystrophy. Nonetheless, for the time being, at least, Nastech's play-it-safe approach to drug development seems to be where the money is. Helping men and women get their swerve on may not be the most heroic goal, but it's sure to set hearts aflutter among deflated lovers and Nastech stockholders as they wait for biotech's more adventurous second act.

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